2. What are the molecular mechanisms in patients with RAS pathway mutations that lead to myeloproliferation in patients with JMML?How do newly-identified secondary mutations and non-coding RNA affect JMML?

Murine models, biochemical analyzes, functional studies to determine what parts of the pathway compensate for each other;Evaluation of mutations in hematopoietic cell sub-populations; Utilize CRISPR to add new mutations to existing mutations.

2. Does targeted therapy of disruptive signaling networks, inclusive of RAS, lead to a durable clinical response?

Biochemistry, cell culture, murine models, clinical trials

3. Have we tested a promising drug and then put it into the clinic quickly, thereby avoiding expensive and time-consuming testing of drugs that are promising but will not be able to be put into the clinic?

4. Have we conducted robust pre-clinical testing of MEK or PI3K inhibitors in murine models before attempting to move these drugs into trials? – completed; some inhibitors work and this data has been published, but they are not yet in clinical trials

9. Is there any role for post-SCT chemotherapy or kinase inhibitor therapy?

Complex experiments in murine models; international clinical trials

10. What is the natural history of germline mutations and what is the propensity to develop JMML and other diseases? (CBL)- removed from Roadmap due to feeling that this question is not as urgent as others in terms of progressing towards a cure

A Ras pathway clinic at NIH

About the JMML Research Roadmap

The JMML Research Roadmap is a vehicle through which affected families, new researchers, and donors alike can visualize the way forward for JMML research. It shows some of the most important current questions about JMML. Answering these questions now will help doctors better understand how JMML works and improve their care for patients.

The JMML Foundation Medical Advisory Committee, chaired by Dr. Christian Kratz of the University of Freiburg, Germany, divided the many possible roads to a cure into four categories: Pathophysiology, From bench to bedside, Murine models, and Clinical management.

Eighteen critical questions were identified as starting points for future research, and potential strategies for addressing each question related to JMML are presented (see table on next page). As noted by Professor Henrik Hasle of the Aarhus University Hospital, Denmark, “it is very appropriate and useful for putting the different scientific questions into perspective.”

Researchers cannot focus solely on the questions in the Roadmap, however, since their research may lead them into unforeseen directions that deserve follow up. Likewise, individual researchers may choose different strategies to answer these questions according to their areas of expertise and their institutions’ resources. This model, therefore, simply estimates the work that lies ahead on the path to a cure for JMML and is designed for ease of update as new questions, and answers, emerge.

What’s next? The JMML Foundation is using this JMML Research Roadmap now to create a research grant process. Through this process, donated funds will be directed to high pay-off targets on the road to a cure. Estimating the cost to answer any particular research question is impossible, though, as it may take many approaches to find the one that works. For an idea of how much it costs to execute a research project, consider how other nonprofits fund leukemia research:

Leukemia Lymphoma Society (LLS) Career Development Grants: $55,000, $65,000, or $110,000 per year for 3 to 5 years

Leukemia Research Foundation New Investigator Grants: Up to $100,000 per year

LLS Translational Research Grants: Up to $200,000 over 3 years

LLS Specialized Center of Research Grants: Up to $6,250,000 over 5 years

Clearer direction for JMML research. Less uncertainty and greater confidence in the research process. A rallying point for research funding. Increased international coordination. Faster progress to a cure. These are some of our aims, supported by the JMML Research Roadmap. We welcome your thoughts and urge your support to make these goals a reality.